Opioid abuse is a significant global public health problem. Of the over million opiate-dependent subjects today, only less than a quarter of such individuals receive treatment. Pharmacotherapeutic approaches traditionally have targeted 5 opioid receptors since heroin and its metabolites bind with highest affinity to this receptor subtype. Although such treatment strategies have improved substance abuse outcomes, they do not effectively block opiate craving and thus are still associated with high rates of relapse. Using a strategy of indirectly regulating neural systems to modulate opioid-related behavior, our preclinical rodent studies consistently demonstrated that cannabidiol (CBD), a nonpsychoactive component of cannabis, specifically inhibited cue- induced heroin-seeking behavior. CBD's selective effect on drug-seeking behavior was pronounced after 24 hrs and endured even two weeks after the last drug administration following short-term CBD exposure. The fact that drug craving is generally triggered by exposure to conditioned cues suggests that CBD might be an effective treatment for heroin craving, specially given its protracted impact on behavior. CBD has already been shown in various clinical studies to be well tolerated with a wide safety margin in human subjects. CBD thus represents a strong candidate for the development as a potential therapeutic agent in humans for opioid craving and relapse prevention. It is the goal of this exploratory phase of the project to (1) determine the safety and basic pharmacokinetic characteristics of CBD when administered concomitantly with opiate in humans and (2) characterize the acute (24 hr) and short-term (3 days) effects of CBD administration on cue-induced craving in drug-abstinent heroin-dependent subjects using a random double blind design. This exploratory investigation together with ongoing complementary preclinical rodent studies has the potential to significantly impact the development of a novel agent for drug relapse prevention that is critical for ending the continued cycle of substance abuse. PUBLIC HEALTH RELEVANCE: Despite the current available therapies for opioid-dependent patients, most patients relapse. This research project focuses on the development of a novel compound, cannabidiol, to modulate opioid craving in humans based on animal models showing its selective effectiveness to inhibit drug-seeking behavior. The development of a targeted treatment for opioid relapse would be of tremendous medical and public health value.